Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders characterized by three domains of behavioral deficits: impaired social interaction, delayed language development, and motor stereotypy. Although etiologies underlying the heterogeneous clinical manifestations of autism remain unclear, one hypothesis is that ASDs are the result of neurodevelopmental deficits targeting the specific neural circuits/networks that mediate the behaviors affected in ASDs. Our preliminary studies of a mouse model that carries a CNS-specific deficiency of the striatonigral medium spiny neuron (MSN)-enriched transcription factor, Zfp521 (Zfp521cko) show postnatal developmental onset of motor stereotypic behaviors resembling the motor stereotypies associated with ASDs. The motor stereotypies exhibited by the Zfp521cko mice, which include facial/head grooming with the forelimbs, body licking, rapid flapping of one hindlimb, and rapid head twitches, are highly frequent, debilitating, cause self-injurious lesions, and impair an ethologically normal behavior, nest building. Based on these compelling preliminary studies, we hypothesize that Zfp521 orchestrates a critical transcriptional program within the striatonigral MSNs which is crucial for their normal maturation, and that disruption of this molecular program can result in motor stereotypies. To this end, our proposed studies will focus on the following Aims: (1) Genetic rescue of the motor stereotypies and striatal circuitry dysfunction by selective transgenic expression of Zfp521 in striatonigral MSNs or striatopallidal MSNs;and (2) Developmental expression profiling of purified striatonigral MSNs in Zfp521cko, D1-BAC-Zfp521 transgenic mice and wildtype mice using the FACS-array technology. The latter study may help to identify the critical downstream transcriptional targets of Zfp521 in the striatonigral MSNs prior to and after the onset of motor stereotypies. Our proposed study is highly significant since it may provide novel circuitry and molecular insights into the neurodevelopmental basis of motor stereotypy, a critical domain affected in ASDs. Furthermore, the molecular insights gained in the study may be a basis to further study the genetic etiology of motor stereotypy in ASDs and to develop novel therapeutics to ameliorate such behavioral deficits in ASDs and other neuropsychiatric disorders. PUBLIC HEALTH RELEVANCE: Motor stereotypy is a core domain of behavioral impairment in Autism Spectrum Disorders (ASDs). Our study will investigate novel basal ganglia circuitry and molecular mechanisms underlying the neurodevelopmental onset of motor stereotypy using a mouse genetic model. Our study will establish whether selective striatonigral neuron dysfunction may be the cause of motor stereotypy and will identify basal ganglia circuitry specific candidate genes and molecular pathways which may underlie the motor stereotypy in our model. Our study may provide novel molecular and circuitry level neurobiological insights into the pathogenesis and treatment of motor stereotypy in ASDs and related neuropsychiatric disorders.